Human papillomaviruses biochemical and biologic properties

The viral origin of warts and condylomas was established at the beginning of this century by experiments on the transmission of warts by means of cell-free tissue extracts.¹ For a long time, a single virus—the human wart virus—was considered responsible for these lesions,¹ although the multiplicity of human papillomaviruses (HPVs) was suspected on the basis of epidemiologic,² serologie,³ and histologic^4,5 data. It was, thus, generally thought that “the clinical type is determined by the local conditions at the site of infection and not by the virus”¹ and that the clinical evolution of the lesions—in particular, the rare malignant transformation^6,7 of genital condylomas and that of the cutaneous lesions of patients suffering from epidermodysplasia verruciformis (EV)—depended on immunologic, genetic, or extrinsic factors.^1,6,8

The characterization of HPVs and the study of their pathogenic properties have long been hindered by the absence of a cellular system permitting the in vitro replication of these viruses.⁹ During the last few years, new methods of analysis of the viral DNA—in particular, the molecular cloning of viral genomes in a plasmid or in the DNA of a bacteriophage—have permitted considerable improvement in our knowledge of HPVs.^10–12 At least 28 HPV types now are recognized^13–29 (Ostrow, R. personal communication). It seems likely that the different clinical types of lesions classically associated with an HPV are, in fact, distinct diseases caused by specific viruses.^23,30–34 Finally, the discovery of the high frequency of infection of the uterine cervix by an HPV,^36,36 as well as the frequent detection of HPV DNA sequences in neoplasias of the skin,^{16,32,37–39} the external genitalia,^40–46 and the uterine cervix^24,25 have broadened the spectrum of the pathogenicity of PVs for human beings and imposed the idea that infection by specific HPV types is a risk factor for the development of these neoplasias.

After reviewing the physicochemical and biologic characteristics of HPVs and the methods used for their study, we will present recent data on the nomenclature, the pathogenicity, and the oncogenic potential of HPVs.     

Humoral immunity to human Papillomaviruses

Many studies have been performed on humoral wart immunity^1–26 since the antibody response to human papillomavirus (HPV) was demonstrated in the first serologic study in patients in 1965.²⁷ The recently established antigenic heterogeneity of HPVs (see chapter 4) and preferential association of HPVs with clinically different types of warts ^14,28–30 (see also chapter 8) have important implications concerning the immunology of warts that have not been taken into account in most studies performed. Therefore much of this work will have to be repeated using distinct HPV antigens in persons with strictly defined warts, as in recent studies. ^{16–17,20,21,23,25,26} This is a review of the features of humoral immunity to HPVs with special regard to their significance in the appearance and regression of warts, and to their place in wartinduced immune response.     

Epidermodysplasia verruciformis

Epidermodysplasia verrucif ormis (EV) is a rare, lifelong disease induced by a diversity of specific human papillomaviruses (HPVs) including, in some instances, the HPVs which induce plane warts in the general population.^1–4 EV provides a model of cutaneous viral oncogenesis, in which virus and host factors are important determinants.

The disease starts usually in early childhood. The lesions, as a rule, do not appear at birth, even in familial cases, in spite of the heavy viral infection of the mother. The reason for this latency period is not known.     

Cell-mediated immunity to human papillomavirus

Cell-mediated immunity (CMI) was suspected to play an important role in the control of human papillomavirus (HPV) infection, primarily for the regression of lesions, based on a number of clinical observations.¹ The incidence of warts increased during immunosuppressive treatment and in subjects with cell-mediated immune defects^2–8 or malignant diseases such as Hodgkin's disease and chronic lymphatic leukemia.^5,9,10 Clinical investigations have reported the regular regression of warts after inflammation,^11–15 after treatment with transfer factor,¹⁶ dinitrochlorobenzene (DNCB) and a variety of immune adjuvants,^2,17,18 and in a few cases after vaccination.^19–22

Specific CMI has been studied at three different levels. Most investigations have been performed on patients with present warts by using in vitro tests. Some others were carried out with in vivo tests on various groups of patients (bearing warts, regressing warts, past warts) and control subjects. Recent studies reported data on local events suggesting a CMI response. In some cases, the findings on specific CMI were correlated with the presence of circulating antibodies. The purpose of these investigations is to approach a better understanding of the role of cellular immunity in wart regression and the preparation of a potential vaccine for patients with recurrent warts.     

Regression of flat warts and common warts

Wart (human papilloma) is such a common disease that even a child can make a diagnosis at a glance. Furthermore, from our long experience, we are aware that warts often disappear in a short period of time, spontaneously or after various magical rituals that are prevalent in different parts of the world. In Japan, we can find some shrines or temples in every district where ardent worshipers make pilgrimages in search of quick answers to their prayers to cure their warts.

Evaluation of clinical effectiveness of a new therapeutic modality is most difficult because of its high incidence of spontaneous wart resolution. The lesion can be cured even by hypnosis.

Recently, the phenomenon of spontaneous regression of warts was reviewed from the viewpoint of tumor immunology. We now know that in the body, tumors may be rejected by an immune “surveillance” mechanism analogous to resistance to microbial pathogens. Various modalities of immunization procedure or enhancement of host immunity can induce partial or complete resolution of established tumors in both experimental animals and humans. Even malignant tumors, such as melanoma or choriocarcinoma, may disappear spontaneously. Wart is one of the most common tumors in humans and probably the tumor that most commonly shows the phenomenon of spontaneous regression.

Advances in molecular biology and biotechnology have disclosed that, as there are various clinical types of wart, there are many distinct HPV types and that the distinct HPV types are associated with distinct cutaneous and mucosal papillomas.¹ Analogous to animals with the Shope papillomavirus or bovine papillomavirus infections, it is known that some human papillomavirus lesions may undergo malignant transformation.^2,3     

New types of human papillomaviruses and intracytoplasmic inclusion bodies: a classification of inclusion warts according to clinical features, histology and associated HPV types

Summary Two new types of intracytoplasmic inclusion bodies (ICBs) associated with distinct clinical features, and the presence of DNA of distinct types of human papillomaviruses (HPVs) are reported. One hundred and seven cutaneous warts containing ICBs were grouped into three categories according to distinct clinicopathological features: 67 were wart lesions with well-known granular (Gr)-ICB. 1 3 were punctate keratotic lesions with filamentous (Fl)-ICB and 31 were pigmented warts with homogeneous (Hg)-ICB. Molecular biological studies were performed in order to assess a specific association of each group of warts with distinct types of HPV.
HPV-1 DNA sequences were detected in all the lesions with a Gr-ICB. Punctate keratotic lesions with Fl-ICB were associated with HPV-63, which was newly cloned from such a lesion. One of the samples also contained HPV-1 DNA. Pigmentcd warts with Hg-ICBs contained one of the related HPVs, i.e. HPV-4. HPV-60 or a novel type of HPV, HPV-65. Based on these associations, a classification of inclusion warts is proposed.     

Cervical condyloma planum

Condylomata were defined and described as wart-like lesions with papillary projections often observed on the skin and mucosa of the anogenital area. Cytologic, histologic, and colposcopic studies have demonstrated that the condylomatous lesion on the cervix presents itself more frequently as a flat lesion than a classical exophytic papillary one.

Condyloma planum represents a new lesion on the human cervix, not described until 1977.^1,2 The viral etiology of this new type of condyloma has been confirmed in three ways: by the electron microscopic observation of human papillomavirus (HPV) particles, ^1,3–8 by the identification of viral antigen using the peroxidaseantiperoxidase technique,^9–13 and by demonstrating the presence of the HPV DNA sequences using molecular cloning and hybridization techniques.^5,14     

Therapy of pemphigus

Pemphigus is a serious autoimmune skin disease associated with a high morbidity and a significant mortality rate. Prior to the advent of steroid therapy, mortality rates of 70–100% were reported.¹ With the use of corticosteroids and antibiotics, the mortality associated with pemphigus has dropped to 15–44%.^2,3 Currently, where corticosteroids are used in conjunction with immunosuppressives, the mortality rate is approximately 10–20%.⁴

Therapy of a pemphigus patient should include a thorough systematic evaluation. Accurate diagnosis, using clinical, histologic and immunofluorescent parameters, is important because the chemotherapy used can cause severe side effects, and untreated, active pemphigus can be fatal. Exogenous causes of pemphigus, especially drugs,⁵ like penicillamine⁶ and captopril,⁷ should be ruled out. Diseases associated with pemphigus should be considered in the evaluation of the patient.

The exact chemotherapy that should be used to treat each patient optimally is unclear. It is well recognized that corticosteroids are the most helpful agents in many patients, and the drugs of choice in severe or active disease.^8–10 However, severe and often life-threatening side effects are also associated with the prolonged administration of the high doses of corticosteroids used to treat pemphigus.^11,12 Alternative or adjuvant therapies are being used more frequently. This is an attempt to gain control of severe disease not controlled with corticosteroids,^13,14 to reduce maintenance steroid dose,^12,16 or to eliminate steroid therapy in mild disease in order to prevent the long-term side effects of corticosteroids.^9,16

At present at least eight therapeutic modalities have been reported as being effective in therapy of pemphigus: systemic corticosteroids; the immunosuppressive drugs, methotrexate, azathioprine, clyclophosphamide; gold; dapsone; sulfapyridine; and plasmapheresis. Emperic use of these therapies has yielded useful information. Since no prospective or retrospective controlled studies have been done to evaluate the effectiveness of one type of therapy versus another, the optimal combination of these therapies is currently not known.     

HPV-associated intraepithelial neoplasia of external genitalia

Intraepithelial neoplasia of the external genitalia with the histologic features, but not the clinical characteristics, of Bowen's disease, has been described under several names: bowenoid papulosis (BP) of the penis or genitalia,^1,2 pigmented penile papules with carcinoma in situ changes,³ multicentric pigmented Bowen's disease (MPBD),^4,5 multicentric Bowen's disease of the genitalia,⁶ reversible vulvar atypia,⁷ bowenoid atypia of the vulva,⁸ bowenoid dysplasia of the vulva,⁹ early vulvar carcinoma,¹⁰ vulvar neoplasia in the young,¹¹ vulvar intraepithelial neoplasia (VIN),¹² penile intraepithelial neoplasia,¹³ carcinoma in situ of the vulva,¹⁴ multicentric vulvar carcinoma in situ,¹⁵ and intraepithelial carcinoma of the vulva.¹⁶

The term bowenoid papulosis of the penis is adequate, since it stresses the multifocal and papular type of the lesions, their localization, and histologic pattern. The term multicentric pigmented Bowen's disease is suitable for the confluent, usually heavily pigmented, and somewhat proliferative lesions in women. The relationship between BP or MPBD and Bowen's disease is currently substantiated by the detection of the same type of human papillomavirus (HPV) in lesions recognized as BP or MPBD, and in typical cases of genital Bowen's disease ¹⁷ (Obalek S, et al. unpublished observations).     

Imiquimod 5% cream for external genital or perianal warts in human immunodeficiency virus-positive patients treated with highly active antiretroviral therapy: an open-label, noncomparative study

Background  Human immunodeficiency virus (HIV)+ patients have an increased risk of anogenital warts. High-risk (HR) human papillomaviruses (HPVs), especially types 16 and 18, are major risk factors for precancerous and cancerous lesions of the anogenital tract, while low-risk (LR) HPVs are associated with benign lesions. Cure of genital warts with ablative techniques, surgical excision, podophyllotoxin or trichloroacetic acid is frequently difficult. Treatment with imiquimod cream showed a total clearance of external genital or perianal warts in about 50% of immunocompetent subjects. However, total clearance was reduced in HIV+ subjects not treated with highly active antiretroviral therapy (HAART).
Objectives  To assess clinically and by monitoring HPV content the efficacy of 5% topical imiquimod to treat anogenital warts in HIV+ subjects with at least partially restored immune functions.
Methods  Fifty HIV+ patients successfully treated with HAART (total CD4+ cells ≥ 200 cells mm⁻³ and plasma HIV RNA load < 10⁴ copies mL⁻¹) with anogenital warts were included. Imiquimod 5% cream was applied on external genital or perianal warts three times weekly for up to 16 weeks. Warts were tested at entry and after treatment for human LR- and HR-HPV DNA.
Results  Total wart clearance was observed in 16 of 50 (32%) patients at week 16. At enrolment, HPV DNA was present in more than 90% of lesions with a majority of lesions co-infected by HR- and LR-HPV. At study end, the HPV load decreased or became undetectable in 40% of cases studied.
Conclusions  Imiquimod 5% cream did not show safety concerns and is suitable for use in HIV+ subjects with anogenital warts and successful HAART treatment.     

Cutaneous manifestations of human papillomaviruses: a review

Human papillomaviruses (HPVs) are small DNA viruses of the papovavirus family, with more than 100 types already described. Their importance in human disease cannot be overemphasized because these agents are among the most common pathogens in cutaneous infectious diseases and are very important in a subset of predominantly, but not exclusively, genital squamous-cell carcinomas. HPVs can be associated with a variety of cutaneous as well as mucosal manifestations. Some types of HPVs are associated with increased risk of epithelial malignancies; these have been divided into low-risk and high-risk types based on their oncogenic potential. Clinical and histological features of HPV infection vary according to individual susceptibility (e.g., immunosuppressed patients), site of involvement, and type of HPV implicated. The histological features of HPV infection are very easy to identify on sections stained with hematoxylin and eosin. However, many findings usually associated with HPV infection are entirely non-specific. Additional current diagnostic methods for identification of HPV in tissues include techniques based on the detection of viral DNA; namely, in-situ hybridization and polymerase chain reaction (PCR). This article reviews the main clinical and histopathological cutaneous manifestations of HPV infection, including common warts, plantar warts, plane warts, condyloma acuminatum, Bowenoid papulosis, and epidermodysplasia verruciformis. Emphasis is placed on the clinical and histological features of these various manifestations, including a brief discussion about the routinely used laboratory methods for detecting HPV in tissues.     

Human papillomavirus (HPV) types specific of epidermodysplasia verruciformis detected in warts induced by HPV3 or HPV3-related types in immunosuppressed patients.

Epidermodysplasia verruciformis (EV) is characterized by an abnormal genetic predisposition to infection with specific types of human papillomavirus (HPV). Specific defects of the cell-mediated immunity and/or of the control of HPV infection in keratinocytes are assumed to be involved in the development of the disease. As a model to test this hypothesis, we have studied the prevalence of EV-specific HPV in skin warts of 56 immunosuppressed patients. All main types of cutaneous HPV (HPV1, 2, 3, 4, 10, and 28) responsible for skin warts in the general population were detected by blot hybridization. EV-specific HPV (HPV5, 20, and 23) were detected in three patients. Four additional patients were found infected with HPV49, first characterized in the course of this study, and found to be related to EV HPV. A most important finding was that HPV5, 20, 23, and 49 were always codetected with HPV3 or the related types HPV10 and 28. None of the specimens showed the typical clinical morphology of EV lesions. In none of these specimens was the specific cytopathic effect of EV recognized; instead that of HPV3 and related types was seen. No evidence for productive EV HPV DNA replication was obtained for the three specimens that could be further analyzed by in situ hybridization. Our data suggest that HPV3 infection favors infection with EV HPV in immunosuppressed patients but that the full expression of EV HPV is usually restricted as in the general population.     

EPIDERMODYSPLASIA VERRUCIEORMIS IN AFRICANS

Background. Epidermodysplasia verruciformis (EV) is a rare cutaneous disorder characterised by persistent, refractory infection with human papillomaviruses (HPV). Although EV does not seem to have racial or geographic preference, there is a scarcity of reports on its occurrence in Africans. Methods. Twenty Africans with EV were studied, and the literature on this condition in Africans was reviewed. Virologic studies were performed on 10 patients. Results. Three types of lesions were observed: flat warts, pityriasis versicolor-like macules, and seborrheic keratosis-like changes. Malignant transformation occurred in only one patient, HPV–3 was isolated only from flat warts, HPV–5 and HPV–17 were isolated only from pv-like lesions, whereas an Hpv–5-related type was found in all three types of changes, HPV–5-related type revealed DNA that was related but not identical to any of the viruses in the HPV–5 group. This particular type was isolated from all five South African patients with EV in whom virologic studies were performed. Conclusions. The benign nature of EV in dark-skinned Africans has been confirmed. Four HPV types have been isolated, of which HPV-related type was found in all South African patients with EV and in all types of skin changes, regardless of their morphology. African patients with EV frequently present seborrheic keratosis-like changes.     

Detection of high-risk human papillomavirus type 16/18 in cutaneous warts in immunocompetent patients, using polymerase chain reaction

Cutaneous warts are caused by human papillomavirus (HPV). Prevalence studies of the types of HPV present in cutaneous warts have been carried out more frequently in immunosuppressed patients. The present study was designed to study the association of high-risk HPV in cutaneous warts of immunocompetent patients. A total of 45 cases of cutaneous warts from various sites in immunocompetent subjects were analyzed for HPV. Samples included both archival material i.e., paraffin embedded and fresh tissue. Highly sensitive and comprehensive polymerase chain reaction (PCR) methodology for detection of HPV of high oncogenic potential, HPV 16/18, was employed. Human papillomavirus 16 was detected in 3 (6.6%) patients. None of the lesions demonstrated HPV 18. None of the cutaneous warts demonstrated histopathological features associated with dysplasia or neoplasia. The identification of HPV 16 in cutaneous warts, which are benign proliferations of the skin, further expands the spectrum of HPV-linked lesions. It remains of critical interest to determine whether these types are specifically associated with the development of malignant lesions analogous to those seen in anogenital cancer.     

Cutaneous sarcoidosis: Prognosis and treatment

The physician who has made a diagnosis of cutaneous sarcoidosis is faced with three basic questions: (1) Are there lesions in organs other than the skin? (2) Should the patient be given treatment? (3) What will the final outcome of the disease be?

Cutaneous sarcoidosis can be a great imitator of other skin diseases with a wide spectrum of clinical manifestations ranging from small asymptomatic cutaneous lesions that fade spontaneously without scarring, to widespread skin lesions and disease in many organ systems. The latter may be associated with severe symptoms such as pulmonary insufficiency or life-threatening biochemical abnormalities. Approximately two thirds of all patients recover completely or with a minimum of residual changes, while 2–5% of sarcoidosis patients die from the disease.^1,2

It is therefore of interest to review the literature that deals with the course and prognosis of sarcoidosis. It is also important to deal with the association of cutaneous sarcoidosis and other types of sarcoidosis in order to provide the dermatologist with a basis for his or her decision about whether treatment should, in fact, be instituted.     

New developments relating to papillomaviruses]

Molecular hybridization technique and immunofluorescence studies with use of specific immune sera against the purified virions isolated from various types of warts and wart-like lesions of epidermodysplasia verruciformis (EV) made it possible to detect four different types of human papilloma viruses (HPV). The recognition of the viruses is important because of the different morphology of the lesions induced and their various oncogenic potentials. HPV1 is mainly responsible for plantar warts, HPV2 for common (hand) warts, HPV3 has been found both in flat warts and in the variety of EV in which skin lesions are of flat wart type, the course is relatively more benign, and usually malignant transformation is not to be expected. HPV4 was up to now found exclusively in the cases of EV with prevalent red and red-brownish plaques and hyper- and depigmentations similar to those of pityriasis versicolor. In all cases of this variety of EV malignancies occured invariably. In patients with EV, as also in--to a lesser extent--longstanding flat and/or common warts cell mediated immunity was in general lowered, but humoral specific anti-HPV antibodies were usually present. HPV type seems to be of a decisive significance for potential oncogenesis, because in a vast majority of cases EV due to HPV3 no malignancies occured in spite of anergy, whereas malignant transformation has been found in all cases due to HPV4, even in a patient with still preserved, although lowered, CMI.     

Atopic dermatitis

A topic dermatitis in people is a chronic pruritic inflammatory skin condition frequently associated with elevated serum IgE and a family history of atopy.¹ Positive intracutaneous reactions to food and inhalant allergens are seen often; however, the relationship between allergen and disease is not firmly established.² Pruritus may be exacerbated by multiple external factors such as food or inhalant allergens, infections, low humidity, sweating, and topical irritants.³

In veterinary medicine, atopic dermatitis is synonymous with atopy and refers to a pruritic skin disease resulting from a type I hypersensitivity in response to environmental allergens.^4–6 This condition is separate from food allergy, which can present with similar clinical findings. The condition has been most extensively studied in the dog, but has also been recognized in cats, sheep, and horses.^4,7

There are many similarities between atopic dermatitis in people and dogs. Because of these similarities, veterinary dermatologists look to the human literature for insights into the pathophysiology and treatment of the disease. This article discusses the pathophysiology, clinical signs, diagnosis, and treatment of canine atopy.     

Ocular sarcoidosis

Ocular involvement in sarcoidosis is the second most common manifestation of the disease, preceded only by pulmonary abnormalities with hilar adenopathy. Ocular disease is the presenting manifestation in 9% of cases,¹ and 25–50% of patients with systemic sarcoidosis will at some time show ocular involvement.^1–3 Chronic ocular sarcoidosis may correlate with cutaneous lesions in 38% of cases. All patients with suspected sarcoidosis should have a thorough ophthalmologic examination.     

Childhood Condyloma Acuminatum: Association with Genital and Cutaneous Human Papillomaviruses

Abstract: We studied 25 children, age 7 months to 12 years 6 months, with anogenltal warts, and their parents. In most children the warts were localized in the anal area, In 3 of 18 girls perianally and on the vulva, and in 4 girls exclusively on the vulva. Southern blot hybridization studies disclosed an association of condylomata with human papllormavlruses (HPV) 6 and 11 in 74% and HPV 2 In 17.4% ol patients. The clinlcal features were similar in warts Induced by genital and cutaneous HPVs. Even the HPV 2-associated warts in the vulva of two girls were typical of condyloma acuminatum.
In all children with HPV 2-induced condytomata, cutaneous common warts coexisted, also induced by HPV 2. However, three mothers had cutaneous warts, and the children's condylomata were associated with HPV 6. Thus, the mere presence of skin warts in family members does not rule out other sources of infection. Sexual abuse was suspected in four girls and two boys, but was not confirmed in any. Nonsexual transmission could occur by persons with the lesions taking care of children. Perinatal transmission also appears to be an important route of infection In small babies. Infection In utero was probable In one girl in whom anal warts appeared in the first week of life and whose mother had cervical condylomata during pregnancy. This study provides further confirmation of possible nonsexual transmission of genital HPVs and the not infrequent association of childhood condylomata with HPV 2.     

Clinical features of pemphigus

Pemphigus is an autoimmune, blistering disease that affects the skin and mucous membranes.¹ It affects all ages. Pemphigus has been reported in children and young adults. The mean age of onset is the sixth decade in most large series, the range being 12–88 years.^2–4 The majority of patients are often in their fourth, fifth, and sixth decades. Thus it appears that pemphigus attacks individuals at the peak of their adult lives. This often has a deleterious effect on the psychology of the patient and the patient's family. Age of anset is important because the prognosis in older patients is not as good as that in younger patients.⁵

Pemphigus affects men and women equally. The incidence is slightly higher in Jewish women than men.⁶ When large series are compared, and patients below the age of 20 are studied, it appears that there is a predilection for women in that group.⁷

The exact incidence of pemphigus is unknown. Since it is not a reportable disease it is difficult to establish the incidence. This reproblem is further compounded by the fact that several drugs are now believed to induce pemphigus (Chapter 4). The establishment of a registry would greatly facilitate the study not only of incidence but other epidemiological features and clinical perspectives as well.

In 1941, less than 1% of all cases seen in a large New York City hospital dermatology clinic accounted for pemphigus⁶; however, at that time, pemphigus was not differentiated from other blistering diseases.⁸ In 1976 in southern Arizona, the incidence was reported to be 0.5 cases per 100,000 population per year.⁹ In 1977 in a study from Hartford County in Connecticut, the annual incidence was 0.42 cases per 100,000 people in general.¹⁰ In the same area, the incidence was 3.2 per 100,000 in the Jewish population. It is generally believed that the incidence is significantly higher in patients of Jewish descent or origin. In a study from Jerusalem, the incidence was reported to be 1.62 cases per 100,000 population.¹¹ Pemphigus has been reported worldwide, and it affects all races.

It is important to emphasize that pemphigus is a rare disease. It is nonetheless one of the few potentially fatal skin diseases. Early diagnosis is often associated with good response to therapy and a better prognosis. Direct and indirect immunofluorescent studies have greatly facilitated the diagnostic armamentarium of the clinician. The availability of these tests by mail has increased their practical utilization.

There are four described variants of pemphigus: (1) pemphigus vulgaris, (2) pemphigus vegetans, (3) pemphigus foliaceus, and (4) pemphigus erythematosus.

The four variants have different clinical presentations. The clinical presentation is dissimilar insofar as that each variant can be clinically differentiated. If the right kind of lesion is biopsied, they can frequently be differentiated histologically. The four variants can also be differentiated in most cases on direct immunofluorescence. On indirect immunofluorescence, the staining pattern is quite similar. It is universally agreed that pemphigus vegetans is a variant of pemphigus vulgaris.¹² Similarly, pemphigus erythematosus is considered a variant of pemphigus foliaceus.¹²